Objective: This study prospectively investigated disease activity, functional disability and health-related quality of life (HRQoL ) in South Africans with early RA, and sought predictors of clinical response at 12 months to traditional disease modifying anti-rheumatic drugs (DMARD) treatment. In addition, the relationships between disease activity, circulating cytokines, the presence of auto-antibodies, the shared epitope (SE), and rheumatoid nodules (RN) were explored. Methods: A cohort of 171 patients with early (≤ 2 years) RA who were DMARD-naïve at inception were prospectively assessed for response to DMARDs over a 12-month period using the simplified disease activity index (SDAI), the Health Assessment Questionnaire-disability index (HAQ-DI) and the Short Form-36 (SF-36). At inception, rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibodies (aCCP) were measured and genomic DNA was analysed using high-resolution PCR typing of the HLA-DR1 allele. Circulating cytokines and growth factors were measured using the Bio-Plex® suspension array system. Results: The 171 patients (140 females) at baseline had a mean age of 47 years, mean symptom duration of 12 months and had severe disease with a mean SDAI of 39, HAQ of 1.7, and globally low SF-36 scores. In the 134 patients seen at 12 months, despite significant improvements, only 28% achieved low disease activity, and 69% still had substantial functional disability (HAQ-DI >0.5), and 66% had suboptimal mental health (SF-36 mental composite score <66.6). Baseline predictors of poor outcomes included unemployment, low level of schooling, female sex, high HAQ-DI and pain scores, and a low haemoglobin level. The 6-months SDAI was better than the baseline SDAI in predicting the 12-month SDAI. The sensitivity and specificity of the aCCP test was 83%, and 85%, and the best specificity seen when both RF and aCCP were positive (95%). SE alleles were found in 92% of patients, and were strongly associated with aCCP, with disease activity and with proinflammatory cytokines. Circulating cytokines in RA reflect a multifaceted increase in immune reactivity with strong correlations between these cytokines, and auto-antibodies, in particular in the subgroup of patients with high disease activity. Subcutaneous RN were seen in 23% of patients, and were associated with more severe joint disease, and significantly higher levels of Th1 and macrophage derived cytokines, with significantly higher vascular endothelial growth factor levels. Conclusions: In this, the first prospective study of RA in sub-Saharan Africa, patients had severe RA, with a high disease burden at baseline and a high proportion carrying the SE allele, aCCP and rheumatoid nodules, with a multifaceted increase in circulating pro-inflammatory cytokines and growth factors. A large proportion of early RA patients have ongoing disease activity, substantial functional disability and suboptimal mental health despite 12 months of DMARD therapy. These findings, together with the high number of patients lost to follow-up, underscore the need for better disease control including an aggressive tight control strategy, and biologic therapy, and for patient- centred rehabilitation programmes with close links to psycho-social services.

Diss. (sammanfattning) Umeå : Univ., 2006. / Härtill 4 uppsatser.

Thesis (doctoral)--Lund University, 1997. / Added t.p. with thesis statement inserted. Includes bibliographical references.

Thesis (doctoral)--Lund University, 1997. / Added t.p. with thesis statement inserted. Includes bibliographical references.

Thesis (Ph. D.)--University of Washington, 1999. / Vita. Includes bibliographical references (leaves 80-96).

Biological disease-modifying anti-rheumatic drugs (DMARDs) for the treatment of Rheumatoid Arthritis, particularly TNF-α inhibitors, have been shown to improve patient outcome by slowing or halting radiographic damage. However, similar to most immunemodulators, there is an increased risk of infections co-incident with Tumour necrosis factor (TNF)-α inhibitor use, particularly the risk of activated latent tuberculosis infection (LTBI). Therefore, local and international guidelines recommend pre-screening for tuberculosis (TB) prior to the initiation of TNF-α therapy in rheumatoid arthritis (RA) patients. Also of critical importance in South Africa is the need for clinicians to be aware of environmental risk factors such as TB being highly endemic. Thus, a qualitative analysis was performed to investigate rheumatologists’ perceptions of TB co-incident with TNF-α inhibitors. Method: Physicians (n=18) practising rheumatology in the private and public healthcare sectors in Gauteng were interviewed to obtain their perceptions and attitudes related to TB co-incident with TNF-α inhibitor use. Interviews were audio-recorded and the transcripts analysed using thematic content analysis. Results: The determinants of health equity: Affordability, accessibility and availability of medicines (specifically TNF-α inhibitors) was reported to be different for the public care versus the private care patient. The high cost of TNF-α inhibitors warranted funding predominantly by the private medical schemes. A higher occurrence of latent TB infection was reported by physicians practising in the public or combined practice compared to the occurrence of LTBI in the private sector (21.4%versus 1.5%). The majority of study participants advocated pre-screening of TB, prior to the initiation of TNF-α inhibitors, in RA. However, it was suggested that because of the high occurrence of LTBI in the public sector, Isoniazid preventative therapy (IPT) should be compulsory, irrespective of the patient’s TB status, for the duration of TNF-α therapy. Most study participants supported local South African Rheumatism and Arthritis Association (SARAA) guideline recommendation to re-screen for TB by chest x-ray (CXR), every 6 months. However, the value of re-screening using diagnostic tools, purified protein derivative (PPD) skin test or interferon-gamma release assays (IGRAs) was queried due to the possibility of false readings. The occurrence of associated active TB in RA patients on TNF-α inhibitors was reported to be 0.07% in the private or combined practice versus 3.00% in the public sector. Forty percent of TB cases were reported to be extra-pulmonary. Despite active vigilance, some physicians reported that active TB month occurred months after the cessation of TNF-α inhibitor therapy. [Similar findings were observed from the British Society for Rheumatology Biologics Register (BSRBR)]. The majority of patients that developed TB co-incident with TNF-α inhibitors were treated successfully with TB chemotherapy. Only 1 of 12 patients died of extra-pulmonary TB, following compassionate use of infliximab in public care. Conclusion: Physicians practising rheumatology in Gauteng were of the opinion that there is a TB risk associated with the use of TNF-α inhibitors for the management of rheumatoid arthritis, as South Africa is a TB endemic country. Most acknowledged that these biological DMARDs were efficacious in slowing or halting radiographic progression in rheumatoid arthritis, but emphasised the need to take steps to prevent TB reactivation in the immuno - compromised RA patients and to remain overtly vigilant for active TB. In clinical practice, physicians mentioned that the monitoring and management of TB associated with TNF-α inhibitors appears to follow the socio-economic status of the RA patient and that distinct recommendations should be made for the public healthcare as well as the private healthcare sectors. Different opinions emanated from different physicians relating to the adequacy of local SARAA guidelines for the prevention of TB associated with TNF-α inhibitors. Some physicians mentioned that local guidelines were sufficient, whilst other physicians mentioned that the diagnostic tools were inadequate in the South African setting and that additional precautions should be taken in the form of IPT for the full duration of TNF-α therapy for all candidates, irrespective of TB status determined during pre-screening. As the science of biological DMARDs evolves with the rapid development of new medicinal therapies, physicians showed a preference to consider alternative non TNF-α biological DMARDs that had a lower risk of associated TB, specifically in high-risk RA patients. Physicians’ overall perception of the management of RA with TNF-α inhibitor therapy was that the risk-benefit assessment of these interventions, as well as patient preference and economic considerations should be taken into account.

Objectives: To determine the impact of human immunodeficiency (HIV) infection on rheumatoid arthritis (RA) disease activity. Patients & Methods: Retrospective record review of RA patients who HIV sero-converted, compared to a HIV negative RA control group. DAS28-ESR and -CRP scores were collected at the initial presentation (T0), time when HIV diagnosis made (TH) and the last clinic visit (TL). Results: Forty three HIV positive RA patients were included. At TL disease activity was similar between the groups, despite methotrexate (MTX) being continued in only 11.6% of the HIV group (vs. 83.7% in the control group, p=0.0002). In the HIV group, all clinical parameters improved except the ESR, which accounted for the significantly higher DAS28-ESR compared to the DAS28-CRP at TL (p=0.004). At TL only 13.9% HIV patients had ongoing moderate to high disease activity. Conclusion: Overall disease activity improved with HIV seroconversion in spite of stopping MTX in the majority of patients. The DAS28-ESR overestimated disease activity compared to DAS28-CRP following HIV seroconversion.

PG receptor and COX gene expression patterns and LPS induced PG production have been investigated in human macrophages and osteoclasts as cell models to study rheumatoid arthritis. The results suggest that PG receptors DP₂, EP₁ and EP₃ may not be directly involved in macrophage-mediated inflammatory responses and osteoclast-mediated bone erosion due to the absence of receptor expression. Because of the undetectable levels of natural ligand, IP receptor effects are dependent on the availability of PGI₂ secreted from other types of cells in the close vicinity. Meanwhile, DP₁, EP₂, EP₄, FP and TP receptors, and their natural agonists, may play important and diverse roles in these cells. TXA₂ is the most abundant prostanoid found in these cells with or without LPS stimulation. The TP receptor pathway in inflammation and bone resorption may have been previously overlooked. AGN-211377 was discovered with a unique pharmacological profile, which provided antagonism at specific proinflammatory PG receptor subtypes with the rank order of TP &gt; DP₁ ≥FP &gt;EP₁ &gt; DP₂ and no apparent antagonism on EP₂, EP₃, and IP receptors. AGN-211377 significantly and dose-dependently suppresses LPS- or TNFα-induced release of 12 proinflammatory cytokines/ chemokines in macrophages, and osteolysis activity in osteoclasts. Collectively, these results suggest the existence of prostanoid receptors DP₁ FP, and TP in human macrophages and osteoclasts, which are likely to play a proinflammatory role. AGN-211377 is at least as effective as diclofenac (a NSAID) and rofecoxib (a COX1B) in suppression of proinflammatory cytokine/chemokine production in macrophages, and in suppression of osteoclast function. Moreover, AGN-211377 may represent a safer replacement for COX1Bs. The therapeutic advantages of AGN-211377 can be extended beyond RA treatment.

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2005. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 5 uppsatser.